Impact of red blood cell transfusion and hemoglobin threshold on 1-year mortality among surgical sepsis survivors: A propensity score matching study.

BACKGROUND: Despite the fact that red blood cell (RBC) transfusion is commonly applied in surgical intensive care unit (ICU), the effect of RBC transfusion on long-term outcomes remains undetermined. We aimed to explore the association between RBC transfusion and the long-term prognosis of surgical sepsis survivors. METHODS: This retrospective study was conducted on adult sepsis patients admitted to a tertiary surgical ICU center in China. Patients were divided into transfusion and non-transfusion groups based on the presence of RBC transfusion. Propensity score matching (PSM) and inverse probability of treatment weighting (IPTW)were performed to balance the potential confounders. RESULTS: A total of 1421 surgical sepsis survivors were enrolled, including 403 transfused patients and 1018 non-transfused patients. There was a significant difference in 1-year mortality between the two groups (23.1 â€‹% vs 12.7 â€‹%, HR: 1.539, 95 â€‹% confidence interval [CI]: 1.030-2.299, P â€‹< â€‹0.001). After PSM and IPTW, transfused patients still showed significantly increased 1-year mortality risks compared to non-transfused individuals (PSM: 23.6 â€‹% vs 15.9 â€‹%, HR 1.606, 95 â€‹% CI 1.036-2.488 â€‹P â€‹= â€‹0.034; IPTW: 20.1 â€‹% vs 12.9 â€‹%, HR 1.600, 95 â€‹% CI 1.040-2.462 â€‹P â€‹= â€‹0.032). Among patients with nadir hemoglobin below 70 â€‹g/L, 1-year mortality risks in both groups were similar (HR 1.461, 95 â€‹% CI 0.909-2.348, P â€‹= â€‹0.118). However, among patients with nadir hemoglobin above 70 â€‹g/L, RBC transfusion was correlated with increased 1-year mortality risk (HR 1.556, 95 â€‹% CI 1.020-2.374, P â€‹= â€‹0.040). CONCLUSION: For surgical sepsis survivors, RBC transfusion during ICU stay was associated with increased 1-year mortality, especially when patients show hemoglobin levels above 70 â€‹g/L.

Deciphering tertiary lymphoid structure heterogeneity reveals prognostic signature and therapeutic potentials for colorectal cancer: a multicenter retrospective cohort study.

BACKGROUND: Tertiary lymphoid structures (TLSs) exert a crucial role in the tumor microenvironment (TME), impacting tumor development, immune escape, and drug resistance. Nonetheless, the heterogeneity of TLSs in colorectal cancer (CRC) and their impact on prognosis and treatment response remain unclear. METHODS: We collected genome, transcriptome, clinicopathological information, and digital pathology images from multiple sources. An unsupervised clustering algorithm was implemented to determine diverse TLS patterns in CRC based on the expression levels of 39 TLS signature genes (TSGs). Comprehensive explorations of heterogeneity encompassing mutation landscape, TME, biological characteristics, response to immunotherapy, and drug resistance were conducted using multi-omics data. TLSscore was then developed to quantitatively assess TLS patterns of individuals for further clinical applicability. RESULTS: Three distinct TLS patterns were identified in CRC. Cluster 1 exhibited upregulation of proliferation-related pathways, high metabolic activity, and intermediate prognosis, while Cluster 2 displayed activation of stromal and carcinogenic pathways and a worse prognosis. Both Cluster 1 and Cluster 2 may potentially benefit from adjuvant chemotherapy. Cluster 3, characterized by the activation of immune regulation and activation pathways, demonstrated a favorable prognosis and enhanced responsiveness to immunotherapy. We subsequently employed a regularization algorithm to construct the TLSscore based on 9 core genes. Patients with lower TLSscore trended to prolonged prognosis and a more prominent presence of TLSs, which may benefit from immunotherapy. Conversely, those with higher TLSscore exhibited increased benefits from adjuvant chemotherapy. CONCLUSIONS: We identified distinct TLS patterns in CRC and characterized their heterogeneity through multi-omics analyses. The TLSscore held promise for guiding clinical decision-making and further advancing the field of personalized medicine in CRC.

Long-term Changes in Low Anterior Resection Syndrome in Survivors of Rectal Cancer: Longitudinal Follow-up of a Randomized Controlled Trial.

BACKGROUND: Postoperative bowel dysfunction, also known as low anterior resection syndrome, is common in rectal cancer survivors and significantly impacts quality of life. Although long-term longitudinal follow-up is lacking, improvement of the syndrome is commonly believed to happen only within the first 2 years. OBJECTIVE: This study aimed to depict the longitudinal evolvement of low anterior resection syndrome beyond 3 years and explore factors associated with changes. DESIGN: Longitudinal long-term follow-ups were performed for the single center with the largest cohort within the multicenter FOWARC randomized controlled trial. SETTING: A quaternary referral center. PATIENTS: Individuals diagnosed with rectal cancer who received long-course neoadjuvant chemotherapy or chemoradiotherapy, followed by sphincter-preserving radical proctectomy. MAIN OUTCOME MEASUREMENTS: Change of low anterior resection syndrome score and stoma status. RESULTS: Of the 220 patients responding to the first follow-up at a median of 39 months, 178 (80.9%) responded to the second follow-up after a median of 83 months. During this interval, the mean low anterior resection syndrome score improved from 29.5 (95% CI, 28.3-30.7) to 18.6 (95% CI, 16.6-20.6). Fifty-six (31.5%) patients reported improvement from major to no/minor severity, and 6 (3.4%) patients had new stomas because of severe bowel dysfunction. Neoadjuvant radiotherapy ( p = 0.016) was independently and negatively associated with improvement of the score. LIMITATIONS: Loss of follow-up during the long-term follow-ups. CONCLUSIONS: Most rectal cancer survivors with low anterior resection syndrome continued to improve beyond 3 years after proctectomy. Neoadjuvant radiotherapy was negatively associated with long-term improvement of low anterior resection syndrome. See Video Abstract . CAMBIO A LARGO PLAZO DEL SNDROME DE RESECCIN ANTERIOR BAJA EN SUPERVIVIENTES DE CNCER DE RECTO SEGUIMIENTO LONGITUDINAL DE UN ENSAYO CONTROLADO ALEATORIO: ANTECEDENTES:La disfunción intestinal posoperatoria, también conocida como síndrome de resección anterior baja, es común en los sobrevivientes de cáncer de recto y afecta significativamente la calidad de vida. Aunque falta un seguimiento longitudinal a largo plazo, comúnmente se cree que la mejoría del síndrome ocurre sólo dentro de los primeros dos años.OBJETIVO:Este estudio tiene como objetivo representar la evolución longitudinal del síndrome de resección anterior baja más allá de los 3 años y explora los factores asociados con el cambio.DISEÑO:Se realizaron seguimientos longitudinales a largo plazo para el único centro con la cohorte más grande dentro del ensayo controlado aleatorio multicéntrico FOWARC.AJUSTE:Un centro de referencia cuaternario.PACIENTES:Individuos diagnosticados con cáncer de recto que recibieron quimioterapia neoadyuvante de larga duración o quimiorradioterapia, seguida de proctectomía radical con preservación del esfínter.PRINCIPALES MEDICIONES DE RESULTADO:Cambio en la puntuación del síndrome de resección anterior baja y el estado del estoma.RESULTADOS:De los 220 pacientes que respondieron al primer seguimiento con una mediana de 39 meses, 178 (80,9%) respondieron al segundo seguimiento después de una mediana de 83 meses. Durante el intervalo, la puntuación media del síndrome de resección anterior baja mejoró de 29,5 (intervalo de confianza [IC] del 95%: 28,3-30,7) a 18,6 (IC del 95%: 16,6-20,6). 56 (31,5%) pacientes informaron una mejoría de mayor a ninguna gravedad, y 6 (3,4%) pacientes tuvieron un nuevo estoma debido a una disfunción intestinal grave. La radiación neoadyuvante (p = 0,016) se asoció de forma independiente y negativa con la mejora de la puntuación.LIMITACIONES:Pérdida de seguimiento durante los seguimientos a largo plazo.CONCLUSIÓN:La mayoría de los sobrevivientes de cáncer de recto con síndrome de resección anterior baja continuaron mejorando más allá de los 3 años después de la proctectomía. La radiación neoadyuvante se asoció negativamente con la mejora a largo plazo del síndrome de resección anterior baja. (Traducción-Dr Yolanda Colorado ).

Structured postoperative handover protocol improves efficiency and quality of interdisciplinary communication and nursing care in surgical intensive care unit: a randomized controlled trial.

This study aimed to evaluate the effectiveness of a structured postoperative handover protocol for postoperative transfer to the SICU. This study was a randomized controlled trial conducted in a comprehensive teaching hospital in China. Patients who were transferred to the SICU after surgery were randomly divided into two groups. The intervention group underwent postoperative structured handover protocol, and the control group still applied conventional oral handover. A total of 101 postoperative patients and 50 clinicians were enrolled. Although the intervention group did not shorten the handover duration (6.18 ± 1.66 vs 5.94 ± 1.91; P = 0.505), the handover integrity was significantly improved, mainly reflected in fewer information omissions (1.44 ± 0.97 vs 0.67 ± 0.62; P < 0.001), fewer additional questions raised by ICU physicians (1.06 ± 1.04 vs 0.24 ± 0.43; P < 0.001) and fewer additional handovers via phone call (16% vs 3.9%; P = 0.042). The total score of satisfaction of the intervention group was significantly higher than that of the control group (76.44 ± 7.32 vs 81.24 ± 6.95; P = 0.001). With respect to critical care, the incidence of stage I pressure sore within 24 h was lower in the intervention group than in the control group (20% vs 3.9%, P = 0.029). Structured postoperative handover protocol improves the efficiency and quality of interdisciplinary communication and clinical care in SICU.Trial registration This study was registered in China on January 8th, 2022 at Chinese Clinical Trial Registry (ChiCTR2200055400).

Developing an Interpretable Machine Learning Model to Predict in-Hospital Mortality in Sepsis Patients: A Retrospective Temporal Validation Study.

BACKGROUND: Risk stratification plays an essential role in the decision making for sepsis management, as existing approaches can hardly satisfy the need to assess this heterogeneous population. We aimed to develop and validate a machine learning model to predict in-hospital mortality in critically ill patients with sepsis. METHODS: Adult patients fulfilling the definition of Sepsis-3 were included at a large tertiary medical center. Relevant clinical features were extracted within the first 24 h in ICU, re-classified into different genres, and utilized for model development under three strategies: "Basic + Lab", "Basic + Intervention", and "Whole" feature sets. Extreme gradient boosting (XGBoost) was compared with logistic regression (LR) and established severity scores. Temporal validation was conducted using admissions from 2017 to 2019. RESULTS: The final cohort included 24,272 patients, of which 4013 patients formed the test cohort for temporal validation. The trained and fine-tuned XGBoost model with the whole feature set showed the best discriminatory ability in the test cohort with AUROC as 0.85, significantly higher than the XGBoost "Basic + Lab" model (0.83), the LR "Whole" model (0.82), SOFA (0.63), SAPS-II (0.73), and LODS score (0.74). The performance in varying subgroups remained robust, and predictors, such as increased urine output and supplemental oxygen therapy, were crucially correlated with improved survival when interpretability was explored. CONCLUSIONS: We developed and validated a novel XGBoost-based model and demonstrated significantly improved performance to LR and other scores in predicting the mortality risks of sepsis patients in the hospital using features in the first 24 h.

Impact of long-course neoadjuvant radiation on postoperative low anterior resection syndrome and stoma status in rectal cancer: long-term functional follow-up of a randomized clinical trial.

BACKGROUND: Neoadjuvant radiation has been increasingly associated with postoperative bowel dysfunction, including low anterior resection syndrome (LARS). Although permanent stoma often results from severe bowel dysfunction and significantly impacts quality of life, the presence of stoma paradoxically excludes patients from functional follow-up. Hence, stoma status is rarely reported along with LARS, while assessment of both is essential for the comprehensive evaluation of bowel dysfunction in long-term survivors of rectal cancer. METHOD: Patients enrolled into the Neoadjuvant FOLFOX6 Chemotherapy with or without Radiation in Rectal Cancer (FOWARC) multicentre randomized clinical trial were randomized to receive long-course neoadjuvant chemoradiotherapy (nCRT) or chemotherapy (nCT) followed by sphincter-saving proctectomy and longitudinal follow-up. The primary outcome of the trial was disease-free survival. LARS score and stoma status were assessed secondarily for postoperative bowel function in the largest single-centre cohort of the trial. RESULTS: Overall, 327 patients with locally advanced rectal cancer were enrolled in the original trial and 203 responded after a median follow-up of 83.4 months, of whom 24 (11.8 per cent) had persistent stoma, and 48 patients (23.6 per cent) reported major LARS. Compared with the nCT group, the nCRT group reported more persistent stomas (16.5 per cent versus 4.9 per cent, P = 0.014), and more major LARS in patients without persistent stoma (34.7 per cent versus 16.7 per cent, P = 0.003). The combined prevalence of persistent stoma and major LARS was significantly higher in the nCRT group (45.5 per cent versus 20.7 per cent, P < 0.001). Long-course neoadjuvant radiation (OR 2.20, 95 per cent c.i. 1.10 to 4.40, P = 0.027), height of anastomosis (OR 0.74, 95 per cent c.i. 0.61 to 0.91, P = 0.004), and anastomotic leak (OR 4.97, 95 per cent c.i. 2.24 to 11.05, P < 0.001) were associated with persistent stoma and major LARS in multivariate analysis. CONCLUSION: More than one-third of patients receiving sphincter-saving proctectomy reported major LARS or persistent stoma at long-term follow-up. Long-course neoadjuvant radiation, low anastomosis, and postoperative leak are independent risk factors for persistent stoma and major LARS.

Neoadjuvant PD-1 blockade with toripalimab, with or without celecoxib, in mismatch repair-deficient or microsatellite instability-high, locally advanced, colorectal cancer (PICC): a single-centre, parallel-group, non-comparative, randomised, phase 2 trial.

BACKGROUND: PD-1 blockade is highly effective in patients with mismatch repair-deficient or microsatellite instability-high metastatic colorectal cancer. The role of single-agent PD-1 blockade in the neoadjuvant setting for resectable mismatch repair-deficient or microsatellite instability-high colorectal cancer remains unclear. We investigated the efficacy and safety of PD-1 blockade with toripalimab, with or without the COX-2 inhibitor celecoxib, as neoadjuvant treatment for mismatch repair-deficient or microsatellite instability-high, locally advanced, colorectal cancers. METHODS: The PD-1 Inhibitor in Microsatellite Instability Colorectal Cancer (PICC) trial was a single-centre, open-label, parallel-group, non-comparative, randomised, phase 2 study undertaken at the Sixth Affiliated Hospital of Sun Yat-sen University (Guangzhou, China). Eligible patients were aged 18-75 years, had histologically confirmed mismatch repair-deficient or microsatellite instability-high colorectal cancer, had clinical stage T3-T4 or any T with lymph node positivity (N+), Eastern Cooperative Oncology Group performance score of 0 or 1, and adequate haematological, hepatic, and renal function. Participants were randomly assigned (1:1), without any stratification or balanced blocking, to receive toripalimab 3 mg/kg intravenously on day 1, with or without celecoxib 200 mg orally twice daily from day 1 to 14 of each 14-day cycle, for six cycles before surgical resection. Adjuvant treatment with toripalimab with or without celecoxib was permitted at the investigators' discretion. The primary endpoint was the proportion of patients with pathological complete response, defined as tumours without any viable tumour cells in the resected primary tumour sample and all sampled regional lymph nodes. All efficacy and safety analyses were assessed in the modified intention-to-treat population, which included all patients who were randomly assigned to treatment and who received at least one dose of toripalimab. This trial is registered with ClinicalTrials.gov, NCT03926338, and is ongoing. FINDINGS: Between May 1, 2019, and April 1, 2021, 53 patients were screened, of whom 34 were randomly assigned to either the toripalimab plus celecoxib group (n=17) or the toripalimab monotherapy group (n=17). As of data cutoff (Aug 10, 2021), median follow-up was 14·9 months (IQR 8·8-17·0). All patients received study treatment and underwent surgical resection; there were no treatment-related surgical delays. All 34 patients had an R0 resection (>1 mm resection margin). 15 of 17 patients (88% [95% CI 64-99]) in the toripalimab plus celecoxib group and 11 of 17 patients (65% [38-86]) in the toripalimab monotherapy group had a pathological complete response. All patients continued to receive adjuvant toripalimab with or without celecoxib for a total perioperative duration of 6 months and were alive and free of recurrence at data cutoff. During neoadjuvant treatment, ten (59%) patients in the toripalimab plus celecoxib group and ten (59%) in the toripalimab monotherapy group had grade 1-2 treatment-related adverse events. Only one (3%) of 34 patients, who was in the toripalimab plus celecoxib group, had a grade 3 or higher treatment-related adverse event during the neoadjuvant phase, which was grade 3 increased aspartate aminotransferase levels. In the adjuvant phase, only one (3%) of 34 patients, who was in the toripalimab monotherapy group, had a grade 3 or higher treatment-related adverse events, which was grade 3 increased aspartate aminotransferase and alanine aminotransferase levels. INTERPRETATION: Neoadjuvant toripalimab with or without celecoxib could be a potential therapeutic option for patients with mismatch repair deficient or microsatellite instability-high, locally advanced, colorectal cancer. This treatment was associated with a high pathological complete response rate and an acceptable safety profile, which did not compromise surgery. Longer term follow-up is needed to assess effects on survival-related endpoints. FUNDING: The National Key R&D Program of China, the National Natural Science Foundation of China, and the Chinese Society of Clinical Oncology-Junshi Biosciences Oncology Immunity Research. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Improvement of low anterior resection syndrome beyond 2 years after total mesorectal excision.

AIM: Bowel dysfunction after sphincter-preserving proctectomy, also known as low anterior resection syndrome (LARS), has significant impact on survivors of rectal cancer. This study aimed to assess the temporal change of LARS beyond 2 years after proctectomy, which has not been fully studied. METHODS: We longitudinally enrolled consecutive patients who had received total mesorectal excision in a tertiary academic medical center, with preoperative neoadjuvant therapy if indicated. LARS score was longitudinally assessed by two serial follow-ups, with a fixed interval of 18 months. RESULTS: Overall, 107 patients responded for the first follow-up after a median of q20 months, 96 of whom responded for the second follow-up after a median of 38 months. At the first follow-up, 48 patients (44.9%) reported major LARS, compared with 23 (24.0%) at the second follow-up (p < 0.001). Mean LARS score improved from 27.3 to 18.6, mostly from "urgency" (12.2 vs. 6.2, p < 0.001) and "clustering of stools" (9.7 vs. 7.7, p = 0.001). Anastomosis less than 3 cm from the anal verge was independently associated with LARS improvement. CONCLUSION: Bowel dysfunction continues to improve 2 years after total mesorectal excision, with most symptom relief in urgency and stool clustering, especially in patients with lower anastomosis.

Comparison of guidelines on rectal cancer: exception proves the rule?

The standard of care for early or locally advanced rectal cancer is promoted by multiple clinical practice guidelines globally, but the considerable differences between the guidelines may cause confusion. We compared the latest updated clinical practice guidelines from five professional societies/authorities: National Comprehensive Cancer Network, American Society of Colorectal Surgeons, European Society of Medical Oncology, Chinese National Health Commission, and Chinese Society of Clinical Oncology. Key evidence is discussed for a better understanding of some seemingly contradictory recommendations.

Astragaloside IV alleviates mouse slow transit constipation by modulating gut microbiota profile and promoting butyric acid generation.

Gut microbiota and short-chain fatty acids (SCFAs) are associated with the development of various human diseases. In this study, we examined the role of astragaloside IV in modulating mouse gut microbiota structure and the generation of SCFAs, as well as in slow transit constipation (STC). An STC model was established by treating mice with loperamide, in which the therapeutic effects of astragaloside IV were evaluated. The microbiota community structure and SCFA content were analysed by 16S rRNA gene sequencing and gas chromatography-mass spectrometry, respectively. The influence of butyrate on STC was assessed using a mouse model and Cajal cells (ICC). Astragaloside IV promoted defecation, improved intestinal mobility, suppressed ICC loss and alleviated colonic lesions in STC mice. Alterations in gut microbiota community structure in STC mice, such as decreased Lactobacillus reuteri diversity, were improved following astragaloside IV treatment. Moreover, astragaloside IV up-regulated butyric acid and valeric acid, but decreased isovaleric acid, in STC mouse stools. Butyrate promoted defecation, improved intestinal mobility, and enhanced ICC proliferation by regulating the AKT-NF-κB signalling pathway. Astragaloside IV promoted intestinal transit in STC mice and inhibited ICC loss by regulating the gut microbiota community structure and generating butyric acid.

Modified Stapled Transanal Rectal Resection Procedure for Limited Rectal Prolapse: A Viable Alternative to the Delorme Operation.

Purpose. The optimal surgical approach for full-thickness rectal prolapse (FTRP) remains controversial. In China, patients with limited FTRP (<5 cm in length) are usually managed by perineal surgery. We retrospectively assessed the outcome of Delorme's procedure and compared it with modified stapled transanal rectal resection (STARR). Methods. The study was conducted in 2 public tertiary referral centers in China with modified STARR or Delorme's procedure performed by experienced surgeons. Outcomes assessed recurrence, operative times, blood loss, complications, length of hospital stay, and continence and constipation scoring. Results. Between December 2012 and May 2019, 65 patients were assessed, including 48 with modified STARR (group 1) and 17 with Delorme's procedure (group 2). The median follow-up was 22 months (range, 3-86 months). The mean operative time for group 1 was 37.4 ± 17.5 minutes vs 74.3 ± 30.6 minutes for group 2 (P < .001). The blood loss for group 1 was significantly lower than that for group 2 (17.4 ± 15.9 mL vs 27.8 ± 16.7 mL, respectively; P = .028). There was no significant difference between groups in recurrence (group 1 18.8% vs group 2 23.5%; P = .944) with no effect of operation type. Both procedures showed improvement in constipation and continence scoring with a similar impact. Conclusions. Modified STARR and the Delorme operation are comparable in managing limited FTRP with superior results in operative time and blood loss for STARR.

Density and distribution of lymphocytes in pretherapeutic rectal cancer and response to neoadjuvant therapy.

BACKGROUND: Lymphocytic density in rectal cancer has been reported to be associated with therapeutic response, but the role of the lymphocytic distribution pattern remains to be determined. This study aimed to evaluate the association between the distribution and density of lymphocytes in rectal-cancer tissue with tumor response to neoadjuvant therapy. METHODS: We retrospectively analysed 134 patients with rectal cancer receiving neoadjuvant therapy within a prospectively maintained cohort. Pretherapeutic biopsy samples were stained with immunohistochemistry (CD4 and CD8). Densities of intratumoral periglandular lymphocytes (IPLs) and tumor-infiltrating lymphocytes (TILs) were assessed separately. Logistic-regression analysis was used to assess associations of lymphocyte densities with tumor regression grade (TRG), controlling for clinicopathological, molecular, and regimen features. RESULTS: Compared with cases in the lowest quartile of CD8+ TILs, those in the highest quartile were significantly associated with better TRG (multivariate odds ratio, 0.23; 95% confidence interval, 0.07 to 0.76; P < 0.001). In contrast, CD8+ IPLs, CD4+ IPLs, and CD4+ TILs were not significantly associated with TRG (P = 0.033, 0.156, and 0.170, respectively). Sensitivity analyses detected no interaction between CD8+ TILs and regimen of neoadjuvant radiation (P interaction = 0.831) or chemotherapy (P interaction = 0.879) on TRG. CONCLUSIONS: Our data suggest that CD8+ TILs, but not IPLs, are independently associated with response to neoadjuvant therapy, regardless of the regimen of radiation or chemotherapy.

[Comparison of postoperative bowel function between patients undergoing transanal and laparoscopic total mesorectal excision].

OBJECTIVE: To compare the effects of transanal total mesorectal excision (taTME) and laparoscopic total mesorectal excision (laparoscopic TME) on patients' postoperative long-term bowel function. METHODS: A retrospective cohort study was used in this study. We analyzed the clinical data of 134 patients with locally advanced mid-low rectal cancer, who underwent transanal TME or laparoscopic TME in the TaLaR randomized controlled trial at the Sixth Affiliated Hospital, Sun Yat-sen University from April 2016 to November 2017. Inclusion criteria included age of 18 to 80 years old, distance from tumor low margin to anal edge ≤10 cm, preoperative staging of T1-3NxM0, and single rectal adenocarcinoma. Exclusion criteria included local recurrence, distant metastases, abdominoperineal resection, unreduced stoma, new stoma, less than 1 year after protectomy or stoma reduction, or preoperative poor anal function or incontinence. Patients were divided into taTME group and laparoscopic TME group. The taTME group received hybrid transanal and transabdominal approach performed simultaneously. The effects of surgical procedures on postoperative bowel function were evaluated with LARS (low anterior resection syndrome) scale, where 0-20 was defined as " no LARS" , 21-29 as " minor LARS" , and 30-42 as " major LARS" . Univariate and multivariate logistic regression analyses were performed to determine the risk factors associated with major LARS, with surgical approach as a pre-selected variate. RESULTS: A total of 107 patients were included. Of the 54 patients in the taTME group, 35 were male, median age was 57.2 (26.0-77.0) years old, and 22 cases had a tumor less than 5 cm from anal verge. Of the 53 patients in the laparoscopic TME group, 35 were male, median age was 62.0 (33.0-73.0) years old, and 25 cases had a tumor less than 5 cm from anal verge. All baseline clinical data including age, gender, preoperative staging, and tumor height were comparable between the two groups (all P>0.05). All operations in both groups were performed successfully. The operation time, intra-operative blood loss, postoperative anastomotic complication, postoperative hospital stay were comparable between the two groups (all P>0.05), except for a lower diverting stoma rate in the taTME group [37.0% (20/54) vs. 64.2% (34/53), χ²=7.866, P=0.005]. Of the 107 patients, 27 (25.2%) had no LARS, 32 (29.9%) had minor LARS, and 48 (44.9%) had major LARS, after a median follow-up of 17.2 (12.1-30.4) months. No significant difference was found between the two groups in overall bowel function [major LARS: 48.1% (26/54) vs. 41.5% (22/53), Z=-0.994, P=0.320]. Compared with the laparoscopic TME group, the taTME group experienced worse clustering of stools [68.5% (37/54) vs. 45.3% (24/53), Z=-2.354, P=0.019]. However, there were no significant differences between the two groups in terms of gas incontinence, liquid stool incontinence, frequency of defecation, and urgency (all P>0.05). Multivariate analysis identified preoperative radiotherapy (OR=5.073, 95% CI: 1.336 to 19.259, P=0.017) and anastomotic height (OR=3.633, 95% CI: 1.501 to 8.802, P=0.004) as independent risk factors for major LARS, but no impact of taTME on LARS (OR=1.442, 95% CI: 0.638 to 3.261, P=0.379). CONCLUSIONS: Compared with laparoscopic TME, taTME has similar outcomes of postoperative long-term bowel function. Preoperative radiotherapy and anastomotic height, but not surgical approach, are independent risk factors for postoperative bowel function.

Impact of Long-Course Neoadjuvant Radiation on Postoperative Low Anterior Resection Syndrome and Quality of Life in Rectal Cancer: Post Hoc Analysis of a Randomized Controlled Trial.

BACKGROUND: Neoadjuvant radiation is recommended for locally advanced rectal cancer, with proven benefit in local control but not in disease-free survival. However, the impact of long-course radiation on postoperative bowel function and quality of life (QOL) remains controversial. This study aimed to investigate the impact of long-course neoadjuvant radiation on bowel function and QOL, and to identify risk factors for severe bowel dysfunction. METHODS: Patients who underwent long-course neoadjuvant chemoradiotherapy (nCRT) or chemotherapy (nCT) followed by radical low anterior resection for locally advanced rectal cancer were recruited from the FOWARC randomized controlled trial. Low anterior resection syndrome (LARS) score and European Organisation for Research and Treatment of Cancer (EORTC) C30/CR29 questionnaires were used to assess bowel function and QOL, respectively. RESULTS: Overall, 220 patients responded after a median follow-up of 40.2 months, of whom 119 (54.1%) reported major LARS, 74 (33.6%) reported minor LARS, and 27 (12.3%) reported no LARS. Compared with the nCT group, the nCRT group reported more major LARS (64.4% vs. 38.6%, p < 0.001) and worse QOL. Long-course neoadjuvant radiation (OR 2.20, 95% CI 1.24-3.91; p = 0.007), height of anastomosis (OR 0.74, 95% CI 0.63-0.88; p < 0.001), and diverting ileostomy (OR 2.59, 95% CI 1.27-5.30; p = 0.009) were independent risk factors for major LARS. CONCLUSIONS: Long-course neoadjuvant radiation, along with low anastomosis, are likely independent risk factors for postoperative bowel function and QOL. Our findings might have implications for alleviating LARS and improving QOL by informing selection of neoadjuvant treatment.

Vitamin D status after colorectal cancer diagnosis and patient survival according to immune response to tumour.

BACKGROUND: High-level plasma 25-hydroxyvitamin D [25(OH)D] has been associated with lower colorectal cancer incidence and mortality. Considering evidence indicating immunomodulatory effects of vitamin D, we hypothesised that survival benefits from high systemic vitamin D level might be stronger for colorectal carcinoma with lower immune response to tumour. METHODS: Using 869 colon and rectal cancer cases within the Nurses' Health Study and Health Professionals Follow-up Study, we assessed the prognostic association of postdiagnosis 25(OH)D score [derived from diet and lifestyle variables to predict plasma 25(OH)D level] in strata of levels of histopathologic lymphocytic reaction. The Cox proportional hazards regression model was adjusted for potential confounders, including microsatellite instability, CpG island methylator phenotype, LINE-1 methylation, PTGS2 (cyclooxygenase-2) expression and KRAS, BRAF and PIK3CA mutations. RESULTS: The association of postdiagnosis 25(OH)D score with colorectal cancer-specific mortality differed by levels of peritumoural lymphocytic reaction (pinteraction = 0.001). Multivariable-adjusted mortality hazard ratios for a quintile-unit increase of 25(OH)D score were 0.69 [95% confidence interval (CI), 0.54-0.89] in cases with negative/low peritumoural lymphocytic reaction, 1.08 (95% CI, 0.93-1.26) in cases with intermediate peritumoural reaction and 1.25 (95% CI, 0.75-2.09) in cases with high peritumoural reaction. The survival association of the 25(OH)D score did not significantly differ by Crohn's-like lymphoid reaction, intratumoural periglandular reaction or tumour-infiltrating lymphocytes. CONCLUSIONS: The association between the 25(OH)D score and colorectal cancer survival is stronger for carcinomas with lower peritumoural lymphocytic reaction. Our results suggesting interactive effects of vitamin D and immune response may contribute to personalised dietary and lifestyle intervention strategies.

MicroRNA let-7, T Cells, and Patient Survival in Colorectal Cancer.

Experimental evidence suggests that the let-7 family of noncoding RNAs suppresses adaptive immune responses, contributing to immune evasion by the tumor. We hypothesized that the amount of let-7a and let-7b expression in colorectal carcinoma might be associated with limited T-lymphocyte infiltrates in the tumor microenvironment and worse clinical outcome. Utilizing the molecular pathological epidemiology resources of 795 rectal and colon cancers in two U.S.-nationwide prospective cohort studies, we measured tumor-associated let-7a and let-7b expression levels by quantitative reverse-transcription PCR, and CD3+, CD8+, CD45RO (PTPRC)+, and FOXP3+ cell densities by tumor tissue microarray immunohistochemistry and computer-assisted image analysis. Logistic regression analysis and Cox proportional hazards regression were used to assess associations of let-7a (and let-7b) expression (quartile predictor variables) with T-cell densities (binary outcome variables) and mortality, respectively, controlling for tumor molecular features, including microsatellite instability, CpG island methylator phenotype, LINE-1 methylation, and KRAS, BRAF, and PIK3CA mutations. Compared with cases in the lowest quartile of let-7a expression, those in the highest quartile were associated with lower densities of CD3+ [multivariate odds ratio (OR), 0.40; 95% confidence interval (CI), 0.23-0.67; Ptrend = 0.003] and CD45RO+ cells (multivariate OR, 0.31; 95% CI, 0.17-0.58; Ptrend = 0.0004), and higher colorectal cancer-specific mortality (multivariate hazard ratio, 1.82; 95% CI, 1.42-3.13; Ptrend = 0.001). In contrast, let-7b expression was not significantly associated with T-cell density or colorectal cancer prognosis. Our data support the role of let-7a in suppressing antitumor immunity in colorectal cancer and suggest let-7a as a potential target of immunotherapy. Cancer Immunol Res; 4(11); 927-35. ©2016 AACR.

Association Between Somatostatin Receptor Expression and Clinical Outcomes in Neuroendocrine Tumors.

OBJECTIVE: Somatostatin receptors (SSTRs), products of gene superfamily SSTR1-5, are commonly expressed in neuroendocrine tumors (NETs). Somatostatin analogs (SSAs) bind to SSTRs and are used as therapeutic agents in patients with advanced NETs. We hypothesized that tumor SSTR expression status would be associated with clinical outcomes in NET. METHODS: Expression of the 5 SSTRs was evaluated by immunohistochemistry, using tissue microarrays comprising 173 primary NETs, 24 matched metastases, and 22 metastatic NETs from 195 patients. Cox proportional hazards regression analysis was used to assess the association of SSTR expression status (high vs low) with clinical outcomes, adjusting for potential confounders. RESULTS: High expression of SSTR2 was associated with longer overall survival (OS) in the cohort overall (multivariate hazard ratio, 0.42; 95% confidence interval, 0.21-0.84; P = 0.013). In a subgroup of patients with metastatic small intestine NET treated with SSAs and evaluable for progression, SSTR2 expression was associated with both longer progression-free survival (PFS) and OS. No associations with PFS or OS were observed with expression of other SSTRs. CONCLUSIONS: Our study demonstrated that expression of SSTR2, but not other SSTRs, is associated with longer OS. In patients treated with SSAs, expression of SSTR2 is associated with longer PFS survival.

Vitamin D and colorectal cancer: molecular, epidemiological and clinical evidence.

In many cells throughout the body, vitamin D is converted into its active form calcitriol and binds to the vitamin D receptor (VDR), which functions as a transcription factor to regulate various biological processes including cellular differentiation and immune response. Vitamin D-metabolising enzymes (including CYP24A1 and CYP27B1) and VDR play major roles in exerting and regulating the effects of vitamin D. Preclinical and epidemiological studies have provided evidence for anti-cancer effects of vitamin D (particularly against colorectal cancer), although clinical trials have yet to prove its benefit. In addition, molecular pathological epidemiology research can provide insights into the interaction of vitamin D with tumour molecular and immunity status. Other future research directions include genome-wide research on VDR transcriptional targets, gene-environment interaction analyses and clinical trials on vitamin D efficacy in colorectal cancer patients. In this study, we review the literature on vitamin D and colorectal cancer from both mechanistic and population studies and discuss the links and controversies within and between the two parts of evidence.